Infectious Diseases, 2015; 47: 267–270
CASE REPORT
Tuberculosis reactivation in hepatocellular carcinoma: association with transarterial chemoembolization
Infect Dis Downloaded from informahealthcare.com by Universitaet Zuerich on 05/07/15 For personal use only.
ANN M. LAAKE1,2, ANGELIKE P. LIAPPIS1,2, ELIZABETH GUY3, GAIL KERR4,5,6 & DEBRA A. BENATOR1,2 From the 1Infectious Diseases Section, and 4Rheumatology Section, Medical Service, Veterans Affairs Medical Center, Washington, DC, USA, 2Department of Medicine, The George Washington University Medical Center, Washington, DC, USA, 3Section of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA, 5Division of Rheumatology, Immunology and Allergy, Georgetown University Medical Center, Washington, DC, USA, and 6Department of Rheumatology, Howard University Hospital, Washington, DC, USA
Abstract Transarterial chemoembolization (TACE) is an important therapeutic option for patients with hepatocellular carcinoma (HCC). We discuss five patients with HCC and tuberculosis (TB) reactivation following TACE. Screening patients for latent TB infection at diagnosis of cirrhosis or HCC should be considered because of the immunosuppression inherent in both the diseases and their treatments.
Keywords: Cirrhosis, hepatocellular carcinoma, transarterial chemoembolization, tuberculosis reactivation
Introduction Transarterial chemoembolization (TACE) is a procedure offered to patients with hepatocellular carcinoma (HCC) not amenable to surgical resection. TACE involves catheterization of the hepatic artery supplying the tumor, injection of local chemotherapy and embolization to occlude tumor blood supply. There is no standardized chemotherapeutic regimen, but an anthracycline is commonly included. Systemic corticosteroids are often given concurrently to minimize the effects and severity of ‘post-embolization syndrome’ (PES), a systemic inflammatory reaction caused by tumor necrosis post-TACE [1]. TACE may also cause infectious complications, including hepatic abscess and cholecystitis. Our report describes five cases in which patients developed symptomatic active tuberculosis (TB) after undergoing TACE for non-resectable HCC.
Case reports The clinical characteristics of the patients are summarized in Table I.
Case 1 A 63-year-old US-born man with a self-reported history of positive purified protein derivative test (PPD) for 20 years with an uncertain treatment history, chronic hepatitis C virus (HCV), a history of alcohol abuse, cirrhosis and multifocal HCC treated with three prior TACEs and three radiofrequency ablations (RFAs) presented with cough and shortness of breath. All three TACE procedures were preceded by a single dose of intravenous dexamethasone. A chest radiograph demonstrated a new large right-sided pleural effusion. Thoracentesis revealed a bloody exudative pleural effusion with a neutrophilic predominance. A pleural biopsy showed necrotizing granulomata. Both his sputum and pleural biopsy were acid-fast bacilli (AFB)-smear negative. Empiric therapy was started with rifampin, isoniazid, moxifloxacin and ethambutol, and he experienced clinical improvement. Two weeks later, the pleural fluid culture grew Mycobacterium tuberculosis (MTB). He completed 3 months of isoniazid, rifampin, moxifloxacin and ethambutol before both rifampin and
The views expressed in this article are those of the authors and do not necessarily reflect the policies of the Department of Veterans Affairs. Correspondence: Debra Benator MD, VAMC, 50 Irving Street NW, Washington, DC 20422, USA. E-mail: [email protected]. (Received 22 July 2014 ; accepted 13 November 2014 ) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/00365548.2014.989540
268
A. M. Laake et al.
Table I. Clinical characteristics of patients who developed Mycobacterium tuberculosis (MTB) after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).
Age, gender
Infect Dis Downloaded from informahealthcare.com by Universitaet Zuerich on 05/07/15 For personal use only.
Case
Comorbidities and risk factors for TB reactivation
1
63, male Chronic HCV, cirrhosis, multifocal HCC, alcohol abuse, partially treated LTBI for 20 years
2
64, male Chronic HCV, cirrhosis, esophageal SCC, gout, multifocal HCC alcohol abuse, untreated LTBI for 5 years 65, male Chronic HCV, cirrhosis, multifocal HCC, alcohol abuse, upper lobe fibrotic lung disease 59, male HBV, HCV, multifocal HCC, unknown LTBI status
3
4
5
64, male HBV, cirrhosis, multifocal HCC, previously treated TB
Findings CXR demonstrated a pleural effusion. Pleural fluid and sputum smear negative. Pleural fluid culture positive. Pleural biopsy with granulomas Synovial fluid smear negative. Synovial culture positive. Synovial fluid cytology retrospectively smear positive CT scan demonstrated bilateral upper lobe cavitary lesions. Sputum smear positive and culture positive CXR with upper lobe lung nodule. Sputum smear positive and culture positive Nodules in the lingula and lower lung. Sputum smear positive and culture positive
Time from recent TACE No. of TACE to symptom procedures onset (days)
Outcome
3
93
Deceased, secondary to HCC and liver failure
3
45
Deceased, secondary to hepatorenal syndrome
3
138
Deceased, secondary to HCC and liver failure
2
130
3
90
Deceased, secondary to intra-abdominal hemorrhage Completed MTB treatment, undergoing chemotherapy for HCC
All patients were human immunodeficiency virus (HIV) negative. TB, tuberculosis; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; LTBI, latent tuberculosis infection; SCC, squamous cell carcinoma; HBV, hepatitis B virus; CXR, chest X-ray; CT, computed tomography.
isoniazid were discontinued because of hepatoxicity. He completed an additional 15 months of moxifloxacin and ethambutol. He died 3 months thereafter owing to hepatocellular carcinoma and liver failure.
completed 8 months of therapy and had no further knee pain or gout flares, but was readmitted with hepatorenal syndrome and died soon thereafter. Case 3
Case 2 A 64-year-old US-born man with an untreated latent tuberculosis infection (LTBI) diagnosed by positive PPD for 6 years, gout, chronic HCV, cirrhosis and multifocal HCC was treated with three TACE procedures. He also had an esophageal squamous cell carcinoma, for which had he received radiation therapy and capecitabine 1 year previously. He presented with pain and effusion in the left knee for 1 month, which started 2 months after his last TACE. He received one dose of intravenous dexamethasone before all three TACEs. Arthrocentesis showed an inflammatory effusion with monosodium urate crystals. Aerobic and anaerobic cultures from the synovial fluid were negative. He was initially treated for gouty arthritis with daily colchicine and a 5 day course of oral prednisone. On the 15th day of hospitalization, his synovial culture grew AFB, identified as MTB. Rifampin, moxifloxacin and ethambutol were started, with the patient showing clinical improvement. He
A 65-year-old US-born man with no known history of LTBI but apical scarring in the right upper lobe on previous imaging, chronic HCV, cirrhosis and multifocal HCC treated with three TACEs, two RFAs and 10 months of sorafenib presented with bilateral apical infiltrates followed by fevers, a cough and dyspnea 4.5 months after his last TACE. A sputum smear collected upon admission was positive for AFB, and the culture grew MTB. His interferongamma release assay (IGRA) was positive at that time. The patient received 3 months of isoniazid, rifampin, moxifloxacin and ethambutol, with clinical improvement. Isoniazid was discontinued owing to hepatotoxicity. He developed hepatorenal syndrome and died shortly thereafter. Case 4 A 59-year-old man from Vietnam with hepatitis B virus (HBV), HCV and HCC treated with two
TB reactivation and transarterial chemoembolization previous TACEs presented with hemoptysis. His LTBI status was unknown at the time of his immigration to the USA. He was found to have a spiculated, partially calcified nodule in the right upper lobe. His sputum was AFB smear positive, which culture subsequently grew MTB. Owing to abnormal liver function tests, rifabutin, levofloxacin and ethambutol were started. Despite his initial tolerance of the regimen, 3 months later he developed intra-abdominal bleeding and acute liver and kidney failure. He died 2 days later.
Infect Dis Downloaded from informahealthcare.com by Universitaet Zuerich on 05/07/15 For personal use only.
Case 5 A 64-year-old man from Thailand with a history of treated pulmonary TB, HBV, cirrhosis and HCC treated initially with chemotherapy, upon recurrence, was retreated with chemotherapy and three TACE procedures. He had previously been treated in Vietnam for pulmonary TB; however, specific records could not be obtained. He presented with generalized malaise for 1 month. His chest X-ray showed fibrocalcific changes in the upper lung fields and an opacity in the lingula. An AFB smear of his sputum tested positive and subsequently cultured MTB. He completed treatment for his TB and continues treatment for his HCC. Discussion Our case series suggests that patients with cirrhosis and HCC who undergo TACE may be at very high risk for TB reactivation, resulting in active pulmonary or extrapulmonary TB. HCC is now the third leading cause of cancer deaths in the USA [2]. Given the increasing incidence of HCC, and the increase in use of TACE for the treatment of HCC, this association should be further explored. At one of the two hospitals participating in this case study, three out of eight (38%) active TB cases from 2011–2013 occurred among patients with cirrhosis and HCC receiving TACE, raising concerns of a greater than expected risk of TB reactivation in this population. Of the remaining five patients with TB, none had underlying liver disease. At the same hospital during the same period there were approximately 400 patients living with confirmed HCV and cirrhosis, 100 of whom carried a diagnosis of HCC [3] and 49 of whom had undergone their first TACE procedure [4]. The first three cases came from Washington, DC, where the active TB rate was 5.9 cases per 100 000 people as of the end of 2012 [5]. For further comparison, US-born patients with solid organ tumors have an active TB rate of eight cases per 100 000 patients, compared to 102 cases per 100 000 in nonUS-born patients with solid organ tumors [6].
269
Active pulmonary TB after TACE has been reported in South Korea in three patients, all of whom had pre-existing granulomatous lung disease [7]. In contrast, two of our cases had extrapulmonary TB, one with infectious arthritis and another with pleural disease. Patients who undergo TACE are likely to have established comorbidities that predispose them to TB reactivation. Head, neck and gastric malignancies have been associated with an increased risk of TB reactivation, but an increase in risk has not been associated with HCC [6]. However, cirrhosis, a risk factor for HCC, has been associated with an increased risk of developing active TB [8]. Although systemic immunosuppression is the most likely mechanism of TB reactivation in this population, it is possible that TACE caused localized TB reactivation in the liver. Hematogenous spread to the knee after reactivation in the liver would explain the articular reactivation of case number 2. Evidence of MTB organisms can be found throughout the body in granulomata in people with LTBI. In support, MTB DNA has been detected not only in the lungs of asymptomatic patients, but also in their hepatic and renal tissues [9]. The immune response to MTB relies on Th-1 lymphocytes producing interferon-gamma, which acts on macrophages to enhance intracellular killing [10]. This integral cytokine pathway is affected by many components of the TACE procedure, including its use of anthracyclines [11]. TACE may alter immunological control of TB both in the local hepatic tissue and systemically. Another potential contributor to TB reactivation is the brief administration of systemic corticosteroids that are sometimes used before TACE as prophylaxis against the PES. PES may occur immediately after TACE, and involves fever and abdominal pain due to inflammation from tumor necrosis. In at least two of the five patients, intravenous dexamethasone (10 mg) was administered before each of their TACE procedures. While chronic systemic corticosteroid use is a well-described risk for LTBI reactivation, there is no evidence linking LTBI reactivation and intermittent use of corticosteroids [12]. There was a delay in diagnosis in all five cases. The time from the onset of symptoms to a diagnostic procedure ranged from 9 to 30 days, with another 17–56 days between diagnostic procedures and microbiological diagnosis. Hence, heightened awareness by physicians following the initiation of TACE is required in order to expedite TB diagnosis and treatment. Both the illness associated with active TB disease and its treatment in the setting of severe liver disease are challenging, and significantly impact quality of
Infect Dis Downloaded from informahealthcare.com by Universitaet Zuerich on 05/07/15 For personal use only.
270
A. M. Laake et al.
life at a time when many such patients are at an increased risk of mortality. Cirrhosis and viral hepatitis, both frequently present in patients with HCC, complicate the treatment further by worsening hepatotoxicity associated with TB therapy. HCV has been confirmed as an independent risk factor for drug-induced liver injury (DILI) during TB treatment [13]. Being HBV surface antigen positive has also been associated with increased DILI in some studies [13]. Although not confirmed as an independent risk factor for DILI, cirrhosis can make the outcomes of drug-induced hepatitis worse. Furthermore, the required infection control and TB isolation may limit contact with loved ones. Thus, prevention is optimal. It is not currently the standard of care to screen for LTBI with a PPD or an IGRA in patients beginning treatments for HCC. However, following our experience, we suggest routine screening and treatment for LTBI pre-TACE, preferably at HCC diagnosis, and better yet, at the diagnosis of cirrhosis where there is already evidence for impaired cell-mediated immunity [14]. Although 9 months of daily isoniazid for LTBI carries a higher risk of hepatotoxicity in patients with HCV, HBV and cirrhosis, the regimen of 12 weekly doses of isoniazid and rifapentine, or 4 months of daily rifampin, may offer an effective regimen for LTBI with a lower and more acceptable risk of hepatotoxicity in patients with liver disease [15]. In conclusion, the association of active TB and TACE in all eight of the cases described in this case series, along with other recent case series, suggests that TACE may further increase the risk of TB reactivation among already high-risk cirrhotic patients with HCC. Testing for latent TB is not currently recommended for HCC patients or patients undergoing TACE [16]. Further population-based studies are needed to understand the risks attributable to this increasingly common procedure.
Acknowledgements We thank Dr. Jack Lichy for review of the pathologic findings related to our cases and Dr. Nazia Qazi for her added expertise. Declaration of interest: No competing financial interests exist for the authors.
References [1] Liapi E, Geschwind JF. Intra-arterial therapies for hepatocellular carcinoma: where do we stand? Ann Surg Oncol 2010;17:1234–46. [2] Centers for Disease Control and Prevention (CDC). Hepatocellular carcinoma – United States, 2001–2006. MMWR Morb Mortal Wkly Rep 2010;59:517–20. [3] Veterans Affairs. Hepatitis C Clinical Case Registry reports. [4] Personal communication. [5] Government of the District of Columbia Department of Health. HIV/AIDS, Hepatitis, STD and TB Administration (HAHSTA), Strategic Information Division. 2013 Annual Epidemiology and Surveillance Report. Washington, DC [cited September 24, 2014]. Available from http://doh. dc.gov/node/678522. [6] Kamboj M, Sepkowitz KA. The risk of tuberculosis in patients with cancer. Clin Infect Dis 2006;42:1592–5. [7] Kim YJ, Goh PG, Moon HS, Lee ES, Kim SH, Lee BS, et al. Reactivation of tuberculosis in hepatocellular carcinoma treated with transcatheter arterial chemoembolization: a report of 3 cases. World J Radiol 2012;4:236–40. [8] Thulstrup AM, Mølle I, Svendsen N, Sørensen HT. Incidence and prognosis of tuberculosis in patients with cirrhosis of the liver. A Danish nationwide population based study. Epidemiol Infect 2000;124:221–5. [9] Barrios-Payán J, Saqui-Salces M, Jeyanathan M, AlcántaraVazquez A, Castañon-Arreola M, Rook G, et al. Extrapulmonary locations of Mycobacterium tuberculosis DNA during latent infection. J Infect Dis 2012;206:1194–205. [10] Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev 2000;11:321–33. [11] Hussner J, Ameling S, Hammer E, Herzog S, Steil L, Schwebe M, et al. Regulation of interferon-inducible proteins by doxorubicin via interferon γ-Janus tyrosine kinase-signal transducer and activator of transcription signaling in tumor cells. Mol Pharmacol 2012;81:679–88. [12] Tam LS, Li EK, Wong SM, Szeto CC. Risk factors and clinical features for tuberculosis among patients with systemic lupus erythematosus in Hong Kong. Scand J Rheumatol 2002;31:296–300. [13] Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935–52. [14] Li WY, Jiang YF, Jin QL, Zhang H, Feng XW, Niu JQ. Immunologic characterization of posthepatitis cirrhosis caused by HBV and HCV infection. J Biomed Biotechnol 2010;2010:138237. [15] Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155–66. [16] Centers for Disease Control and Prevention (CDC). Screening for tuberculosis and tuberculosis infection in high-risk populations recommendations of the advisory council for the elimination of tuberculosis. MMWR Morb Mortal Wkly Rep 1995;44(RR-11):18–34.
CASE REPORT
Tuberculosis reactivation in hepatocellular carcinoma: association with transarterial chemoembolization
Infect Dis Downloaded from informahealthcare.com by Universitaet Zuerich on 05/07/15 For personal use only.
ANN M. LAAKE1,2, ANGELIKE P. LIAPPIS1,2, ELIZABETH GUY3, GAIL KERR4,5,6 & DEBRA A. BENATOR1,2 From the 1Infectious Diseases Section, and 4Rheumatology Section, Medical Service, Veterans Affairs Medical Center, Washington, DC, USA, 2Department of Medicine, The George Washington University Medical Center, Washington, DC, USA, 3Section of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA, 5Division of Rheumatology, Immunology and Allergy, Georgetown University Medical Center, Washington, DC, USA, and 6Department of Rheumatology, Howard University Hospital, Washington, DC, USA
Abstract Transarterial chemoembolization (TACE) is an important therapeutic option for patients with hepatocellular carcinoma (HCC). We discuss five patients with HCC and tuberculosis (TB) reactivation following TACE. Screening patients for latent TB infection at diagnosis of cirrhosis or HCC should be considered because of the immunosuppression inherent in both the diseases and their treatments.
Keywords: Cirrhosis, hepatocellular carcinoma, transarterial chemoembolization, tuberculosis reactivation
Introduction Transarterial chemoembolization (TACE) is a procedure offered to patients with hepatocellular carcinoma (HCC) not amenable to surgical resection. TACE involves catheterization of the hepatic artery supplying the tumor, injection of local chemotherapy and embolization to occlude tumor blood supply. There is no standardized chemotherapeutic regimen, but an anthracycline is commonly included. Systemic corticosteroids are often given concurrently to minimize the effects and severity of ‘post-embolization syndrome’ (PES), a systemic inflammatory reaction caused by tumor necrosis post-TACE [1]. TACE may also cause infectious complications, including hepatic abscess and cholecystitis. Our report describes five cases in which patients developed symptomatic active tuberculosis (TB) after undergoing TACE for non-resectable HCC.
Case reports The clinical characteristics of the patients are summarized in Table I.
Case 1 A 63-year-old US-born man with a self-reported history of positive purified protein derivative test (PPD) for 20 years with an uncertain treatment history, chronic hepatitis C virus (HCV), a history of alcohol abuse, cirrhosis and multifocal HCC treated with three prior TACEs and three radiofrequency ablations (RFAs) presented with cough and shortness of breath. All three TACE procedures were preceded by a single dose of intravenous dexamethasone. A chest radiograph demonstrated a new large right-sided pleural effusion. Thoracentesis revealed a bloody exudative pleural effusion with a neutrophilic predominance. A pleural biopsy showed necrotizing granulomata. Both his sputum and pleural biopsy were acid-fast bacilli (AFB)-smear negative. Empiric therapy was started with rifampin, isoniazid, moxifloxacin and ethambutol, and he experienced clinical improvement. Two weeks later, the pleural fluid culture grew Mycobacterium tuberculosis (MTB). He completed 3 months of isoniazid, rifampin, moxifloxacin and ethambutol before both rifampin and
The views expressed in this article are those of the authors and do not necessarily reflect the policies of the Department of Veterans Affairs. Correspondence: Debra Benator MD, VAMC, 50 Irving Street NW, Washington, DC 20422, USA. E-mail: [email protected]. (Received 22 July 2014 ; accepted 13 November 2014 ) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/00365548.2014.989540
268
A. M. Laake et al.
Table I. Clinical characteristics of patients who developed Mycobacterium tuberculosis (MTB) after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).
Age, gender
Infect Dis Downloaded from informahealthcare.com by Universitaet Zuerich on 05/07/15 For personal use only.
Case
Comorbidities and risk factors for TB reactivation
1
63, male Chronic HCV, cirrhosis, multifocal HCC, alcohol abuse, partially treated LTBI for 20 years
2
64, male Chronic HCV, cirrhosis, esophageal SCC, gout, multifocal HCC alcohol abuse, untreated LTBI for 5 years 65, male Chronic HCV, cirrhosis, multifocal HCC, alcohol abuse, upper lobe fibrotic lung disease 59, male HBV, HCV, multifocal HCC, unknown LTBI status
3
4
5
64, male HBV, cirrhosis, multifocal HCC, previously treated TB
Findings CXR demonstrated a pleural effusion. Pleural fluid and sputum smear negative. Pleural fluid culture positive. Pleural biopsy with granulomas Synovial fluid smear negative. Synovial culture positive. Synovial fluid cytology retrospectively smear positive CT scan demonstrated bilateral upper lobe cavitary lesions. Sputum smear positive and culture positive CXR with upper lobe lung nodule. Sputum smear positive and culture positive Nodules in the lingula and lower lung. Sputum smear positive and culture positive
Time from recent TACE No. of TACE to symptom procedures onset (days)
Outcome
3
93
Deceased, secondary to HCC and liver failure
3
45
Deceased, secondary to hepatorenal syndrome
3
138
Deceased, secondary to HCC and liver failure
2
130
3
90
Deceased, secondary to intra-abdominal hemorrhage Completed MTB treatment, undergoing chemotherapy for HCC
All patients were human immunodeficiency virus (HIV) negative. TB, tuberculosis; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; LTBI, latent tuberculosis infection; SCC, squamous cell carcinoma; HBV, hepatitis B virus; CXR, chest X-ray; CT, computed tomography.
isoniazid were discontinued because of hepatoxicity. He completed an additional 15 months of moxifloxacin and ethambutol. He died 3 months thereafter owing to hepatocellular carcinoma and liver failure.
completed 8 months of therapy and had no further knee pain or gout flares, but was readmitted with hepatorenal syndrome and died soon thereafter. Case 3
Case 2 A 64-year-old US-born man with an untreated latent tuberculosis infection (LTBI) diagnosed by positive PPD for 6 years, gout, chronic HCV, cirrhosis and multifocal HCC was treated with three TACE procedures. He also had an esophageal squamous cell carcinoma, for which had he received radiation therapy and capecitabine 1 year previously. He presented with pain and effusion in the left knee for 1 month, which started 2 months after his last TACE. He received one dose of intravenous dexamethasone before all three TACEs. Arthrocentesis showed an inflammatory effusion with monosodium urate crystals. Aerobic and anaerobic cultures from the synovial fluid were negative. He was initially treated for gouty arthritis with daily colchicine and a 5 day course of oral prednisone. On the 15th day of hospitalization, his synovial culture grew AFB, identified as MTB. Rifampin, moxifloxacin and ethambutol were started, with the patient showing clinical improvement. He
A 65-year-old US-born man with no known history of LTBI but apical scarring in the right upper lobe on previous imaging, chronic HCV, cirrhosis and multifocal HCC treated with three TACEs, two RFAs and 10 months of sorafenib presented with bilateral apical infiltrates followed by fevers, a cough and dyspnea 4.5 months after his last TACE. A sputum smear collected upon admission was positive for AFB, and the culture grew MTB. His interferongamma release assay (IGRA) was positive at that time. The patient received 3 months of isoniazid, rifampin, moxifloxacin and ethambutol, with clinical improvement. Isoniazid was discontinued owing to hepatotoxicity. He developed hepatorenal syndrome and died shortly thereafter. Case 4 A 59-year-old man from Vietnam with hepatitis B virus (HBV), HCV and HCC treated with two
TB reactivation and transarterial chemoembolization previous TACEs presented with hemoptysis. His LTBI status was unknown at the time of his immigration to the USA. He was found to have a spiculated, partially calcified nodule in the right upper lobe. His sputum was AFB smear positive, which culture subsequently grew MTB. Owing to abnormal liver function tests, rifabutin, levofloxacin and ethambutol were started. Despite his initial tolerance of the regimen, 3 months later he developed intra-abdominal bleeding and acute liver and kidney failure. He died 2 days later.
Infect Dis Downloaded from informahealthcare.com by Universitaet Zuerich on 05/07/15 For personal use only.
Case 5 A 64-year-old man from Thailand with a history of treated pulmonary TB, HBV, cirrhosis and HCC treated initially with chemotherapy, upon recurrence, was retreated with chemotherapy and three TACE procedures. He had previously been treated in Vietnam for pulmonary TB; however, specific records could not be obtained. He presented with generalized malaise for 1 month. His chest X-ray showed fibrocalcific changes in the upper lung fields and an opacity in the lingula. An AFB smear of his sputum tested positive and subsequently cultured MTB. He completed treatment for his TB and continues treatment for his HCC. Discussion Our case series suggests that patients with cirrhosis and HCC who undergo TACE may be at very high risk for TB reactivation, resulting in active pulmonary or extrapulmonary TB. HCC is now the third leading cause of cancer deaths in the USA [2]. Given the increasing incidence of HCC, and the increase in use of TACE for the treatment of HCC, this association should be further explored. At one of the two hospitals participating in this case study, three out of eight (38%) active TB cases from 2011–2013 occurred among patients with cirrhosis and HCC receiving TACE, raising concerns of a greater than expected risk of TB reactivation in this population. Of the remaining five patients with TB, none had underlying liver disease. At the same hospital during the same period there were approximately 400 patients living with confirmed HCV and cirrhosis, 100 of whom carried a diagnosis of HCC [3] and 49 of whom had undergone their first TACE procedure [4]. The first three cases came from Washington, DC, where the active TB rate was 5.9 cases per 100 000 people as of the end of 2012 [5]. For further comparison, US-born patients with solid organ tumors have an active TB rate of eight cases per 100 000 patients, compared to 102 cases per 100 000 in nonUS-born patients with solid organ tumors [6].
269
Active pulmonary TB after TACE has been reported in South Korea in three patients, all of whom had pre-existing granulomatous lung disease [7]. In contrast, two of our cases had extrapulmonary TB, one with infectious arthritis and another with pleural disease. Patients who undergo TACE are likely to have established comorbidities that predispose them to TB reactivation. Head, neck and gastric malignancies have been associated with an increased risk of TB reactivation, but an increase in risk has not been associated with HCC [6]. However, cirrhosis, a risk factor for HCC, has been associated with an increased risk of developing active TB [8]. Although systemic immunosuppression is the most likely mechanism of TB reactivation in this population, it is possible that TACE caused localized TB reactivation in the liver. Hematogenous spread to the knee after reactivation in the liver would explain the articular reactivation of case number 2. Evidence of MTB organisms can be found throughout the body in granulomata in people with LTBI. In support, MTB DNA has been detected not only in the lungs of asymptomatic patients, but also in their hepatic and renal tissues [9]. The immune response to MTB relies on Th-1 lymphocytes producing interferon-gamma, which acts on macrophages to enhance intracellular killing [10]. This integral cytokine pathway is affected by many components of the TACE procedure, including its use of anthracyclines [11]. TACE may alter immunological control of TB both in the local hepatic tissue and systemically. Another potential contributor to TB reactivation is the brief administration of systemic corticosteroids that are sometimes used before TACE as prophylaxis against the PES. PES may occur immediately after TACE, and involves fever and abdominal pain due to inflammation from tumor necrosis. In at least two of the five patients, intravenous dexamethasone (10 mg) was administered before each of their TACE procedures. While chronic systemic corticosteroid use is a well-described risk for LTBI reactivation, there is no evidence linking LTBI reactivation and intermittent use of corticosteroids [12]. There was a delay in diagnosis in all five cases. The time from the onset of symptoms to a diagnostic procedure ranged from 9 to 30 days, with another 17–56 days between diagnostic procedures and microbiological diagnosis. Hence, heightened awareness by physicians following the initiation of TACE is required in order to expedite TB diagnosis and treatment. Both the illness associated with active TB disease and its treatment in the setting of severe liver disease are challenging, and significantly impact quality of
Infect Dis Downloaded from informahealthcare.com by Universitaet Zuerich on 05/07/15 For personal use only.
270
A. M. Laake et al.
life at a time when many such patients are at an increased risk of mortality. Cirrhosis and viral hepatitis, both frequently present in patients with HCC, complicate the treatment further by worsening hepatotoxicity associated with TB therapy. HCV has been confirmed as an independent risk factor for drug-induced liver injury (DILI) during TB treatment [13]. Being HBV surface antigen positive has also been associated with increased DILI in some studies [13]. Although not confirmed as an independent risk factor for DILI, cirrhosis can make the outcomes of drug-induced hepatitis worse. Furthermore, the required infection control and TB isolation may limit contact with loved ones. Thus, prevention is optimal. It is not currently the standard of care to screen for LTBI with a PPD or an IGRA in patients beginning treatments for HCC. However, following our experience, we suggest routine screening and treatment for LTBI pre-TACE, preferably at HCC diagnosis, and better yet, at the diagnosis of cirrhosis where there is already evidence for impaired cell-mediated immunity [14]. Although 9 months of daily isoniazid for LTBI carries a higher risk of hepatotoxicity in patients with HCV, HBV and cirrhosis, the regimen of 12 weekly doses of isoniazid and rifapentine, or 4 months of daily rifampin, may offer an effective regimen for LTBI with a lower and more acceptable risk of hepatotoxicity in patients with liver disease [15]. In conclusion, the association of active TB and TACE in all eight of the cases described in this case series, along with other recent case series, suggests that TACE may further increase the risk of TB reactivation among already high-risk cirrhotic patients with HCC. Testing for latent TB is not currently recommended for HCC patients or patients undergoing TACE [16]. Further population-based studies are needed to understand the risks attributable to this increasingly common procedure.
Acknowledgements We thank Dr. Jack Lichy for review of the pathologic findings related to our cases and Dr. Nazia Qazi for her added expertise. Declaration of interest: No competing financial interests exist for the authors.
References [1] Liapi E, Geschwind JF. Intra-arterial therapies for hepatocellular carcinoma: where do we stand? Ann Surg Oncol 2010;17:1234–46. [2] Centers for Disease Control and Prevention (CDC). Hepatocellular carcinoma – United States, 2001–2006. MMWR Morb Mortal Wkly Rep 2010;59:517–20. [3] Veterans Affairs. Hepatitis C Clinical Case Registry reports. [4] Personal communication. [5] Government of the District of Columbia Department of Health. HIV/AIDS, Hepatitis, STD and TB Administration (HAHSTA), Strategic Information Division. 2013 Annual Epidemiology and Surveillance Report. Washington, DC [cited September 24, 2014]. Available from http://doh. dc.gov/node/678522. [6] Kamboj M, Sepkowitz KA. The risk of tuberculosis in patients with cancer. Clin Infect Dis 2006;42:1592–5. [7] Kim YJ, Goh PG, Moon HS, Lee ES, Kim SH, Lee BS, et al. Reactivation of tuberculosis in hepatocellular carcinoma treated with transcatheter arterial chemoembolization: a report of 3 cases. World J Radiol 2012;4:236–40. [8] Thulstrup AM, Mølle I, Svendsen N, Sørensen HT. Incidence and prognosis of tuberculosis in patients with cirrhosis of the liver. A Danish nationwide population based study. Epidemiol Infect 2000;124:221–5. [9] Barrios-Payán J, Saqui-Salces M, Jeyanathan M, AlcántaraVazquez A, Castañon-Arreola M, Rook G, et al. Extrapulmonary locations of Mycobacterium tuberculosis DNA during latent infection. J Infect Dis 2012;206:1194–205. [10] Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev 2000;11:321–33. [11] Hussner J, Ameling S, Hammer E, Herzog S, Steil L, Schwebe M, et al. Regulation of interferon-inducible proteins by doxorubicin via interferon γ-Janus tyrosine kinase-signal transducer and activator of transcription signaling in tumor cells. Mol Pharmacol 2012;81:679–88. [12] Tam LS, Li EK, Wong SM, Szeto CC. Risk factors and clinical features for tuberculosis among patients with systemic lupus erythematosus in Hong Kong. Scand J Rheumatol 2002;31:296–300. [13] Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935–52. [14] Li WY, Jiang YF, Jin QL, Zhang H, Feng XW, Niu JQ. Immunologic characterization of posthepatitis cirrhosis caused by HBV and HCV infection. J Biomed Biotechnol 2010;2010:138237. [15] Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155–66. [16] Centers for Disease Control and Prevention (CDC). Screening for tuberculosis and tuberculosis infection in high-risk populations recommendations of the advisory council for the elimination of tuberculosis. MMWR Morb Mortal Wkly Rep 1995;44(RR-11):18–34.
